Opiate drugs are widely use for pain relief during labor and delivery, and their use is associated with a variety of adverse effects in the mother and fetus. The overall goal of this program project grant (PPG) is to develop novel opioid peptide analogs that have fewer adverse effects on the mother and fetus than the opiate alkaloids. It was proposed that maternal-fetal pharmacokinetics and receptor selectivity can be used as two approaches in the design of novel opioid peptide analogs with fewer adverse effects. We hypothesized that placental transfer of opioid analogs across the placenta to the fetus will be more limited compared to opiate alkaloids, and that delta agonists will have fewer adverse effects compared to mu-agonists. Our results confirm that fetal exposure to some opioid peptide analogs is much more limited compared to opiate alkaloids. However, four mu-selective peptide analogs turned out to have minimal adverse effects on the maternal-fetal unit with the exception of a blunting of the baroreflex response to hypertensive stimuli, while three delta-selective peptide analogs turned out to have significant opioid and non-opioid cardiovascular and respiratory effects. The objective of this renewal application is to continue our efforts in developing highly selective mu and delta opioid peptide analogs and to further our understanding of the pharmacokinetics, pharmacodynamic effects, and mechanisms of action of these analogs on the maternal-placental-fetal unit. Our specific aims for the next 5 years are: 1) develop highly selective mu agonists that are effective after intravenous or intrathecal administration and do not penetrate the placenta; 2) develop selective delta peptide analogs that do not have deleterious non-opioid effects; 3) continue to develop appropriate analytical methods to quantitate peptide analogs in maternal and fetal plasma and to measure plasma levels of mu- and delta-selective opioid peptide analogs after intravenous and intrathecal administration; 4) examine the pharmacokinetics and pharmacodynamics of mu and delta opioid peptide analogs on maternal and fetal cardiovascular, respiratory and metabolic functions; and 5) understand the mechanisms underlying the observed pharmacodynamic effects. The strength of this PPG is the cohesive effort in studying the pharmacokinetics and pharmacodynamics of a large number of peptide analogs with different receptor selectivity and physicochemical properties, together with a complete batter of maternal and fetal response parameters, which would permit extensive structure-activity correlations that would form the rationale for future peptide design.